Phase Ib Study Shows Vadastuximab Talirine and 7+3 Combination Is Safe in Patients with Newly Diagnosed AML

Results from a phase Ib study presented at the 2016 ASH Annual Meeting suggest that combining standard 7+3 chemotherapy with the investigational CD33-directed antibody conjugate vadastuximab talirine was safe in patients with newly diagnosed acute myeloid leukemia (AML), and could potentially help improve response and survival rates in this population.

“Although a high percentage of patients achieve an initial complete response (CR) by morphologic criteria [after induction therapy with daunorubicin and cytarabine], a significant number of patients are either primarily resistant to treatment or achieve a morphologic CR with molecular evidence of minimal residual disease (MRD),” the authors, led by Harry P. Erba, MD, PhD, from the University of Alabama at Birmingham, explained. “CD33, a cell surface antigen, is expressed in approximately 90 percent of AML, representing a promising target for therapy regardless of genetic or mutational heterogeneity.”

Dr. Erba and colleagues evaluated the safety and anti-leukemic activity of escalating doses of vadastuximab talirine, also known as 33A, in combination with standard induction therapy for patients (<65 years old) with newly diagnosed AML. 33A was given on days one and four concomitantly with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2).

The investigators assessed response (per International Working Group criteria) and MRD (by multi-parametric flow cytometric assay) on days 15 and 28. A second induction regimen and post-remission therapies were investigator choice, but did not include additional administration of 33A.

At the time of study presentation, 42 patients (36% male; median age = 45.5 years [range = 18-65]) had been treated; four patients received 10+10 mcg/kg of 33A, and 38 patients received 20+10 mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk factors (according to Medical Research Council criteria), and 17 percent of patients had secondary AML.

Patients showed no evidence of increased toxicity or mortality (30- and 60-day mortality rates were 0% and 7%, respectively), and the rates of hematologic adverse events (AEs) “were similar to what would be expected with standard chemotherapy alone,” according to the investigators (TABLE). Grade 1 or 2 non-hematologic AEs included nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no grade ≥3 non-hematologic AEs occurred in >15 percent of patients, and no infusion-related reactions, veno-occlusive disease, or significant hepatotoxicity were observed.

The authors observed three dose-limiting toxicities, all of which occurred at the 20+10 mcg/kg dose level, which was determined to be the maximum tolerated dose of 33A in combination with 7+3.

“Seventy-six percent of our patients achieved a response,” Dr. Erba reported, “and most of those (60%) were complete remissions, meaning that neutrophils recovered to ≥1,000 µ/L – which is very important for preventing infection – and platelets were recovered to over 100,000.” Seventeen percent of patients experienced a CRi, which were all due to incomplete platelet count recovery.

Although the response rates may not be dissimilar to what would be expected with 7+3 alone, notably, the responses were rapid, with the majority of patients who responded to 33A and 7+3 doing so after one cycle of induction therapy. This finding will be particularly important for patients, Dr. Erba noted. “Only thirty out of 32 patients (92%) required one round of chemotherapy to achieve remission … [this] might not be something that leads to FDA approval, but it is important for a patient who cares about the difference between being in the hospital for four weeks versus six to eight weeks if they get two cycles.”

In addition, 25 of the 32 responders (78%) achieved MRD-negative status, which “suggests that we may be able to achieve deeper remissions” with this combination, he said, “and, if we can get patients into an MRD-negative state, maybe the outcomes would improve.”

A randomized trial of 7+3 with or without 33A is planned to start early next year and will hopefully confirm these preliminary findings, Dr. Erba concluded.


Erba H, Levy M, Vasu S, et al. A phase Ib study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Abstract #211. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.